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Dna Methylation And Human Disease

Changes in DNA methylation patterns have been implicated in the development and progression of many types of cancers. Additionally, defects in DNA methylation have been associated with several genetic diseases, including ICF (Immunodeficiency, Centromere Instability, and Facial Anomalies), Rett, and Fragile X syndromes, all of which result in variable degrees of mental retardation. This common effect on neurological function may result from the fact that DNA methylation occurs at high levels in the brain, and implies that the brain requires DNA methylation for proper development.

ICF syndrome is a rare recessive disease characterized by variable immunodeficiency, developmental delays, distinctive facial features, and mental retardation. In 1999 it was found that patients with ICF syndrome have mutations in the DNA methyltransferase gene DNMT3B, located on human chromosome 20q11. These mutations impair the function of DNMT3B, resulting in an overall reduction in DNA methylation, or hypomethylation. This, in turn, leads to destabilization of the centromeres of chromosomes 1, 9, and 16. The alteration in chromosome structure leaves these chromosomes susceptible to DNA breakage and possibly alters the expression of genes located in these regions.

Rett syndrome and Fragile X syndrome are other genetic disorders that result from a disruption in the function of methylated DNA. Rett patients, who are almost all young females, at first develop normally. Later on, however, they develop mental retardation, autism, and movement disorders. These patients have a mutation in the gene for the methyl-binding protein MeCP2. This protein usually represses gene expression by binding tightly to methylated DNA and causing repression.

Fragile X syndrome is the most common form of inherited mental retardation. Fragile X results from an increase in the number of CGG repeats in the promoter region of the FMR1 gene on the X chromosome. When the number of repeated sequences reaches the 200 to 600 copy range, the repeat itself becomes very heavily methylated, leading to silencing of the FMR1 gene. The critical importance of DNA methylation in mammalian development is obvious, given the diseases that result when this process is improperly regulated.

Theresa M. Geiman

and Keith D. Robertson


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Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 3Methylation - Biochemical Features, Cpg Islands, Host Defense, Gene Repression, Gene Imprinting, Dna Methylation And Human Disease